Project Summary/Abstract My research is focused on elucidating the cellular and molecular mechanisms that constrain malignant cancers. It is known that cells possess intrinsic and extrinsic tumor- suppressor mechanisms that are orchestrated by a handful of key tumor-suppressor genes. However, the inability to restore tumor suppressor function at will in established tumors has hampered our understanding of their functions. The project proposed within this K99/R00 award outlines the creation and implementation of novel mouse models that allow gene inactivation and gene restoration to be controlled in a tissue-specific and temporal manner. The research proposed within this application has been shaped by my experiences studying the consequences of telomere dysfunction in a model of Burkitt's lymphoma and by my recent efforts to elucidate the in vivo effects of restoring the p53 tumor-suppressor gene in several models of diverse human cancers. These research projects solidified my interests in pursuing a career studying the fundamental components of human cancer progression. My desire to interrogate the biology of tumor-suppression requires the development of novel genetic systems in which tumor-suppressor gene function can be inactivated and then subsequently restored. The systems that we propose herein utilize autochthonous mouse models and genetically defined human cancer cells. Comparative analysis of these systems will enhance discovery of fundamental mechanisms of tumor suppression by capitalizing on the relevant in vivo setting and the relevant organism in which to study human cancer. The facilities at the Koch Institute at MIT, and the expertise that my mentor, Dr. Jacks, can provide will be invaluable for successful implementation of this project. The goals of these experiments outlined within are: to highlight the therapeutic potential of targeting these tumor-suppressor pathways as a means to eradicate cancer, to identify relevant mechanisms by which tumor-suppressor genes inhibit cancer formation or progression in a variety of tumor types, to uncover biological programs unleashed upon tumor-suppressor gene restoration, and to identify specific novel targets for therapeutic intervention. The research environment in the Jacks Laboratory, MIT, and the surrounding area offers unmatched opportunities for scientific discussion, collaboration, and training. Currently, I supervise an undergraduate student and a technical assistant that work directly with me on experiments pertaining to my research. This is an incredible experience that will endow me with many of the necessary skills to manage an independent laboratory. The scientific community at MIT, the Broad Institute, and Harvard Medical School offers countless seminars and workshops that will continue to foster my scientific development. My immediate goals are to develop the research platform described in this application and to demonstrate its potential to unlock heretofore uncharacterized molecular and cellular mechanisms of tumor suppression. It is my intention to start an independent research program that will capitalize on these in vivo systems by studying multiple tumor-suppressor genes in a variety of important tumor types. For the long-term, I am confident that these experiments will provide a foundation on which my research program can grow. I look forward to educating and recruiting students and postdocs that share my passion for cancer research.